Myelodysplastic Syndromes Staging

Myelodysplastic syndromes (MDS) are a group of clonal myeloid neoplasms characterized by ineffective hematopoiesis that present clinically as cytopenia(s), dysplasia in one or more hematopoietic cell lines in the bone marrow, and risk of transformation to acute myeloid leukemia (AML). ^[1]

See Myelodysplastic Syndromes: Classification, Features, Diagnosis, and Treatment Options, a Critical Images slideshow, to help identify, classify, work up, and treat these disorders.

Evidence of clonality often supports the diagnosis of MDS and may manifest as recurrent karyotypic or molecular genetic abnormalities, although these findings are not necessary to fulfill the diagnostic criteria.

MDS represent several molecularly unique entities whose variation makes constructing a concise and practical framework difficult. However, with ever-increasing knowledge of the biology and molecular heterogeneity of myeloid neoplasms comes the ability to further classify MDS with prognostic and predictive relevance. Furthermore, there is increasing recognition that some higher-risk MDS have considerable biologic and prognostic overlap with MDS-related AML. As such, in 2022, the World Health Organization (WHO) updated its classification of myelodysplastic syndromes, replacing the term "syndromes" with "neoplasms" to reflect the neoplastic biology of these diseases. ^[2]

While the Revised International Prognostic Scoring System (IPSS-R) ^[3] remains the prognostic rubric used in most recent MDS clinical trials, an updated Molecular Prognostic Scoring System (IPSS-M) uses somatic mutation status of genes found on most myeloid malignancy next generation sequencing (NGS) panels to refine prognostication for MDS patients ^[4] .  

WHO classification of MDS

The WHO classification system of MDS relies on incorporating clinical features, peripheral blood and bone marrow findings, and cytogenetic analysis. ^[2] This classification of myeloid neoplasms also includes a collection of heterogeneous neoplasms that share features of MDS and myeloproliferative neoplasms.

These "overlap neoplasms" fall under the classification "myelodysplastic/myeloproliferative neoplasms" (MDS/MPN) and include the following:

• Chronic myelomonocytic leukemia (CMML)
• Myelodysplastic/myeloproliferative neoplasm with neutrophilia
• Myelodysplastic/myeloproliferative neoplasm with SF3B1 mutation and thrombocytosis 
• Myelodysplastic/myeloproliferative neoplasm, not otherwise specified

Although a detailed discussion of the overlap neoplasms is beyond the scope of this review, they share clinical, pathologic, and therapeutic features with MDS and can be treated similarly when they present with more features of MDS than MPN.

The WHO MDS classification comprises three groups, as listed below and detailed in Table 1, below.

MDS with defining genetic abnormalities:

• MDS with low blasts and isolated 5q deletion (MDS-5q)
• MDS with low blasts and SF3B1 mutation (MDS- SF3B1)
• MDS with biallelic TP53 inactivation (MDS-bi TP53)

MDS, morphologically defined:

• MDS with low blasts (MDS-LB)
• MDS, hypoplastic (MDS-h)
• MDS with increased blasts (MDS-IB)
• MDS-IB1, MDS-IB2 and MDS with fibrosis (MDS-f)

Childhood MDS:

• Childhood MDS with low blasts (hypocelular and not otherwise specified)
• Childhood MDS with increased blasts

Table 1. World Health Organization criteria for myelodysplastic neoplasms (2022, 5th edition) (Open Table in a new window)

Each of the MDS categories can be qualified as secondary to predisposing risk factors. Patients with MDS post cytotoxic therapy (MDS-pCT), as subcategory of myeloid neoplasm post cytotoxic therapy (MN-pCT), have blood and bone marrow findings of one of the above diagnostic categories (frequently with multilineage dysplasia) and a past history of exposure to cytotoxic chemotherapy and/or radiation therapy administered for treatment of cancer or nonneoplastic disease.  

Myeloid neoplasms with germ line predisposition may present as MDS and are classified into three major categories, as follows:

• No preexisting disorder or organ dysfunction – germline mutations in  DDX41, CEBPA or TP53
• Preexisting platelet disorder – germline  RUNX1,  ANKRD26, or  ETV6 mutation
• Potential organ dysfunction – germline GATA2 mutation; associated bone marrow failure syndromes (Fanconi anemia, severe congenital neutropenia, Schwachman-Diamond syndrome), telomere biology disorders, RASopathies, Down syndrome, germline SAMD9 mutation, SAMD9L mutation or biallelic BLM variant

Like the fitfth edition WHO Classification, the International Consensus Classification (ICC) of Myeloid Neoplasms and Acute Leukemias was published in 2022 with the goal of classifying myeloid neoplasms among categories with prognostic and therapeutic relevance. ^[5] With regard to MDS, the classification rubrics are highly similar. Key differences in the ICC with regard to MDS are listed below.

Three categories of low-blast MDS (< 2% in PB, < 5% in BM) grouped accoring to extent of dysplastic morphology, absent genetic findings (5q deletion, multi-hit TP53 mutation/loss, mutated SF3B1):

• MDS, not otherwise specified, without dysplasia: MDS without morphologic dysplasia but with at least one cytopenia and MDS-defining cytogenetic changes--monosomy 7, del(7q) or complex karyotype 
• MDS with single lineage dysplasia
• MDS with multi-lineage dysplasia (≥2 dysplastic lineages)

The designation "MDS/AML" recognizes the simlar biology, prognosis, and therapeutic considerations between AML and MDS with increased blasts as defined by the following:

• 10-19% BM or PB blasts
• Absence of AML-defining genetic features that are often associated with dysplastic morphology: mutated NPM1, bZIP CEBPA mutations
• Absence of TP53 mutation

In recognition of the unique, aggressive biology and therapeutic unmet need associated with TP53 mutation/loss, separate categories of myeloid neoplasms with mutated TP53 are designated, as follows:

• MDS with mutated TP53: 0-9% BM/PB blasts and multi-hit TP53 mutation or TP53 mutation and complex karoytype
• MDS/AML with mutated TP53: 10-19% BM/PB blasts and any somatic TP53 mutation with variant allele fraction (VAF) of >10%
• AML with mutated TP53: ≥20% BM/PB blasts or meeting morphologic criteria for pure erythroid leukemia  and any somatic TP53 mutation with VAF of >10%

Revised IPSS (IPSS-R) and Molecular IPSS (IPSS-M)

Although several prognostic scoring systems have been developed, ^{[6, 7]} the most widely used has been the revised IPSS. Compared with the original IPSS, ^[8] the IPSS-R ^[3] refined cytogenetic prognostic categorization and weighted the prognostic score according to the severity of cytopenias in addition to the bone marrow blast percentage. The sum of the assigned points yields a prognostic score, which estimates survival and risk of progression to AML.

In addition to the clinical and pathologic variables included in the IPSS-R, point mutations in genes such as TP53, EZH2, ETV6, RUNX1, and ASXL1 have been consistently shown to identify patients at risk for shortened survival or transformation to acute leukemia. ^[9]  Due to the emerging prognostic relevance of mutations and the increasing availability of next-generation sequencing (NGS) assays, the IPSS-M was developed. ^[4]

The IPSS-M combines clinical, cytogeneti,c and somatic mutational variables and can be calculated using online calculators. Compared with the IPSS-R, the IPSS-M stratifies patients into six (rather than five) prognostic categories: very low, low, moderate low, moderate high, high and very high risk, each discriminating risk of leukemia-free survival, overall survival and leukemic transformation (see Tables 2-4, below). Using somatic mutation data, almost half of patients are re-categorized from one IPSS-R risk stratum to a different higher or lower risk stratum in IPSS-M. For this reason, broad NGS panels that include mutations used in the development of IPSS-M is standard-of-care testing for all newly diagnosed MDS patients. 

Table 2. IPSS-R assignment of score (Open Table in a new window)

 

Table 3. IPSS-R risk groups, by sum of score ^[3] (Open Table in a new window)

 

Table 4. Prognosis of IPSS-M risk groups (Open Table in a new window)